Catalytic olefin metathesis has transformed chemical synthesis and offers exceptionally efficient pathways for synthesis of alkenes. Many biologically active molecules are macrocycles that contain alkenes or other commonly occurring functional groups, such as an epoxide, diol or cyclopropane, which can be accessed via the carbon-carbon double bond. One of the most widely utilized protocols for synthesis of large rings is catalytic ring-closing metathesis (RCM). In most cases, however, macrocyclic RCM proceeds with minimal control of alkene stereoselectivity; this shortcoming is particularly costly in the case of complex molecules, since ring closure is typically performed after a long sequence of transformations.
Catalytic ring-closing metathesis (RCM) is an indispensable method for the preparation of cyclic structures of various sizes (Hoveyda, A. H. & Zhugralin, A. R. The remarkable metal-catalyzed olefin metathesis reaction. Nature 450, 243-251 (2007)); it is one of the most popular strategies used in the total synthesis of a large number of biologically active natural products (Deiters, A. & Martin, S. F. Synthesis of oxygen- and nitrogen-containing heterocycles by ring-closing metathesis. Chem. Rev. 104, 2199-2238 (2004); Nicolaou, K. C., Bulger, P. G. & Sarlah, D. Metathesis reactions in total synthesis. Angew. Chem. Int. Edn 44, 4490-4527 (2005); Gradillas, A. & Perez-Castells, J. Macrocyclization by ring-closing metathesis in the total synthesis of natural products: reaction conditions and limitations. Angew. Chem. Int. Edn 45, 6086-6101 (2006); Gradillas, A. & Pérez-Castells, J. in Metathesis in Natural Product Synthesis (eds Cossy, J., Arsenyadis, S., Meyer, C.)—(Wiley-VCH, 2010)).
However, the stereochemical outcome in RCM reactions is typically not subject to catalyst control; instead, selectivity is based on energetic attributes of the stereoisomers of the product molecules. In the case of small- or medium-ring structures, Z alkenes are strongly favored. With larger rings, on the other hand, the energy difference between the two alkene isomers is often not sufficiently large to allow for high stereoselectivity through thermodynamic control, or the E isomer is strongly preferred. Furthermore, since olefin metathesis is reversible, as the reaction moves towards completion, the higher energy Z isomer might be converted to the lower energy E form through post-RCM isomerization. Accordingly, there remains a need for reliable methods for highly selective synthesis of Z macrocyclic alkenes through RCM.